Fine-particle forms of pharmaceutical substances such as fine powders are frequently associated with technical processing disadvantages. In order to avoid such disadvantages, frequently coarser particles (granules) are provided.
Such particles of pharmaceutical substances can be used to produce dosage forms by for example compressing them alone or together with further components to give tablets. Medicinal substance-containing particles may additionally be used packed into capsules or in the form of a powder for a suspension or solution.
A number of methods are known for producing particles. Solvents are employed in some of the methods. This is disadvantageous because the solvents must be removed again during the method. Even small amounts of remaining solvents may impair the product quality. Organic solvents are additionally undesired from the viewpoint of safety at work and environmental protection.
Solidified melt granules (melt granules) are known as alternative. They are produced by melting and shock solidification, by casting and comminuting or by spray congealing in spray towers. These known methods are, however, associated with disadvantages.
Methods in which a solidified melt is comminuted are rather elaborate because they require stages of melting, solidifying and comminuting separately, for each of which different types of apparatuses are required. In addition, it is rather difficult to obtain particulate material with a particle size distribution. Moreover, the particles obtained by comminution have irregular shapes, thus making further handling difficult.
The production of melt granules by solidifying a melt in a spray tower is also associated with disadvantages. There is typically formation of a relatively large proportion of material of unwanted particle size, which must be separated off and remelted. The resulting particles are ordinarily not uniformly globular, thus impairing their handling properties.
A method of the last-mentioned type is described in EP 0 362 731. The method is carried out by atomizing an active pharmaceutical ingredient melt in a spray chilling tower in order to produce active pharmaceutical ingredient particles. Ibuprofen is employed for example as active ingredient. The particles are obtained by cooling droplets of a melt which is atomized in a spray chilling tower in the presence of crystallization nuclei and is brought into contact with a chilling gas. Desired particles are removed with the aid of a sieve from the powder which is formed.
A number of other patents and patent applications also relate to the production of medicinal substance particles, specifically of ibuprofen particles, and to the use thereof for producing certain dosage forms.
EP 0 362 728 A2 relates to a method for obtaining ibuprofen for direct tableting. In this case, an ibuprofen melt is solidified on a contact-chilling apparatus and then comminuted. Since the production of the particles takes place in two stages, the method is rather elaborate. In addition, the particles have irregular shapes owing to the comminution process.
U.S. Pat. No. 6,322,816 relates to analgesic products with rapid release of active ingredient. A suitable active ingredient is in particular ibuprofen. The active ingredient is present in a special adjuvant matrix.
US 2003/0203026 relates to therapeutic agents, in particular a compressed tablet. This contains a granular component which comprises a plurality of solidified melt granules of a non-steroidal anti-inflammatory drug which has a melting point in the range from 30 to 200° C., and a disintegrant uniformly distributed therein. Ibuprofen is a preferred active ingredient. The melt can be solidified by chilling and then comminuted. Alternatively, the melt can be sprayed through a nozzle in order to make it possible to solidify the material, which is then collected.
US 2005/0003000 relates to a method for forming ibuprofen solids, where additives are added to a solution of ibuprofen and are removed again later.
WO 02/07706 relates to a method for coating solid particles, for example ibuprofen particles. This document is not concerned with the production of these particles employed as starting material.
WO 94/10993 relates to pharmaceutical formulations of ibuprofen. The production of a particulate dosage form is described inter alia, there being provision for addition of an aqueous solution of a binding to ibuprofen.
U.S. Pat. No. 5,320,855 relates to chewable tablets which are produced from granules of a medicament. The granules in turn are produced by rotogranulation of a mixture of a medicinal substance such as ibuprofen and excipients and is provided with particular coatings.
EP 0 290 168 relates to an ibuprofen tablet with sustained release. There is provided in particular an ibuprofen-containing matrix which is obtained by granulating ibuprofen mixed with excipients in powder form using a particular solution as granulation liquid.
EP 0 241 126 relates to a solid pharmaceutical composition which includes granules which consist essentially of an aggregate of ibuprofen crystals. The method generally includes the compaction of crystalline ibuprofen in order to bring about aggregation of the crystalline ibuprofen to form an aggregate material, the comminution of the aggregate material and the selection of granules with the desired size. It is possible for example to produce crystalline ibuprofen by wetting with a solvent. An extrusion then takes place. The granules obtained in this case are dried.
EP 0 230 322 relates to a pharmaceutical composition with sustained release of the active ingredient. Sugar esthers of higher fatty acids are employed in this case. The production method includes mixing and granulating components.
EP 0 250 648 relates to a pharmaceutical product for sustained release of ibuprofen. The product is in the form of tablets which comprise the active ingredient in microspheres. Production takes place by mixing the ibuprofen and a binding to give a homogeneous mixture and moistening with water. The mixture is then shaped to microspheres by extrusion, and tablets are finally produced therefrom.
WO 96/31197 relates to homogeneous mixtures of low-melting medicinal substances and additives for controlled release. One method for producing such a formulation includes the melting of a medicinal substance and an additive at a temperature below 150° C., mixing the medicinal substance and the additive to form a homogeneous mixture, and finally hardening the homogeneous mixture to form a medicinal substance-additive composite material. It is intended to introduce the molten mass into capsules, where it then hardens on cooling.
The prior art further includes proposals for producing granules by using spouted bed apparatuses. Thus, DE 103 22 062 A1 discloses the production of granules from various materials by applying liquids in a solid stream in a spouted bed apparatus. Said application is, however, not concerned either with the specifics of pharmaceutical substances or with the conditions which must be observed when producing particles from a melt.
DE 100 04 939 C1 relates to a controllable gas stream unit for spouted bed apparatuses. The patent is not concerned with the production of melt granules.
WO 2004/108911 A2 relates to methods for producing enzyme granules and to such granules. A spouted bed apparatus is employed for the production. The application is not concerned with melt granules.